17-Beta hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases

ABSTRACT

There are disclosed compounds of the formula (I):  
                 
 
     prodrugs thereof, or pharmaceutically acceptable salts of the compounds or of said prodrugs which are useful as inhibitors of Type 3 17β-Hydroxysteroid Dehydrogenase. Also disclosed are pharmaceutical compositions containing said compounds and their use for the treatment or prevention of androgen dependent diseases.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/330,066, filed Oct. 17, 2001.

BACKGROUND

[0002] 1. Field of the Invention

[0003] The invention relates to novel inhibitors of Type 317β-Hydroxysteroid Dehydrogenase, pharmaceutical compositions containingthe compounds and the use of the compounds for the treatment orprevention of androgen dependent diseases.

[0004] 2. Description of Related Art

[0005] Androgen dependent diseases, for example, diseases whose onset orprogress is aided by androgenic activity, are well known. These diseasesinclude but are not limited to prostate cancer, benign prostatichyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precociouspuberty, adrenal hyperplasia and polycystic ovarian syndrome. Estrogendependent diseases, i.e. diseases whose onset or progress is aided byestrogenic activity are also well known. These include but are notlimited to breast cancer, endometriosis, leiomyoma and precociouspuberty.

[0006] Androgenic and estrogenic activity may be suppressed byadministering androgen receptor antagonists or estrogen receptorantagonists respectively. See e.g. WO 94/26767 and WO 96/26201.Androgenic and estrogenic activity may also be reduced by suppressingandrogen or estrogen biosynthesis using inhibitors of enzymes thatcatalyze one or more steps of such biosynthesis. Type 317β-Hydroxysteroid Dehydrogenase (17β-HSD3) is the primary enzyme thatconverts androstenedione to testosterone in the testes. Androgenic andestrogenic activity may also be reduced by suppressing ovarian ortesticular secretions by known methods. See e.g. WO 90/10462, WO91/00731, WO 91/00733, and WO 86/01105. Type 5 17B-HydroxysteriodDehydrogenase is described in WO 97/11162. Novel inhibitors of both Type3 and Type 5 17B-Hyroxysteroid Dehydrogenase are described in WO99/46279.

[0007] U.S. Pat. No. 5,665,735 discloses compounds useful in thetreatment of asthma, allergy and inflammation, which are of the formula:

[0008] or a pharmaceutically acceptable salt or solvate thereof,wherein:

[0009] or a five-membered heterocyclic aromatic group selected from thegroup consisting of Formulas I to XII:

[0010] wherein X represents O, S.

[0011] U.S. Pat. No. 5,432,175 discloses compounds which possessanti-allergic and anti-inflammatory activity and are of the formula:

[0012] or a five-membered heterocyclic aromatic group containing atleast one in the ring structure,

[0013] T represents CH, C or N,

[0014] Current therapies for the treatment of androgenic and estrogenicdependent diseases include the use of glucocorticoids to block adrenalsecretions, and luteinizing hormone releasing hormone (LHRH) agonistswhich cause medical castration. Both therapies are associated withundesirable side effects. An improved therapy would include compoundsthat specifically inhibit type 3 17β-Hydroxysteroid dehydrogenase, whileavoiding inhibition of other 17β-Hydroxysteroid dehydrogenases. Such animprovement is provided by this invention.

SUMMARY OF THE INVENTION

[0015] The present invention provides novel compounds represented byFormula (I):

[0016] a prodrug thereof, or a pharmaceutically acceptable salt orsolvate of the compound or of the prodrug wherein,

[0017] R¹ is selected from the group consisting of aryl, heteroaryl,arylalkyl, heteroarylalkyl and diphenylalkyl, each optionallysubstituted with one to six groups selected from the group consistingof:

[0018] a) halogen;

[0019] b) —OCF₃ or —OCHF₂;

[0020] c) —CF₃;

[0021] d) —CN;

[0022] e) alkyl or R¹⁸-alkyl;

[0023] f) heteroalkyl or R¹⁸-heteroalkyl;

[0024] g) aryl or R¹⁸-aryl;

[0025] h) heteroaryl or R¹⁸-heteroaryl;

[0026] i) arylalkyl or R¹⁸-arylalkyl;

[0027] j) heteroarylalkyl or R¹⁸-heteroarylalkyl;

[0028] k) hydroxy;

[0029] l) alkoxy;

[0030] m) aryloxy;

[0031] n) —SO₂-alkyl;

[0032] o) —NR¹¹R¹²;

[0033] p) —N(R¹¹)C(O)R¹³,

[0034] q) methylenedioxy;

[0035] r) difluoromethylenedioxy;

[0036] s) trifluoroalkoxy;

[0037] t) —SCH₃ or —SCF₃; and

[0038] u) —SO₂CF₃ or —NHSO₂CF₃;

[0039] R² and R³ are each independently selected from the groupconsisting of: H, —OH, alkoxy, alkyl, cycloalkyl, heterocycloalkyl,cycloalkylalkyl, trifluoroalkyl, heteroalkyl, arylalkyl,heteroarylalkyl, arylalkoxy, heteroarylalkoxy, —(CH₂)_(n)—NR¹¹R¹² and—(CH₂)_(n)—SR¹¹, provided that when X is N, then R² and R³ are each not—OH, alkoxy, arylalkoxy or heteroarylalkoxy;

[0040] R⁴, R⁵, R⁷ and R⁸ are each independently selected from the groupconsisting of: H, —OR¹⁴, —NR¹¹R¹², —N(R¹¹)C(O)R¹³, alkyl, aryl,cycloalkyl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl,

[0041]  provided that when Z and/or X is N, then R⁴, R⁵, R⁷ and R⁸ areeach not —OR¹⁴, —NR¹¹R¹² or —N(R¹¹)C(O)R¹³;

[0042] R⁶ is selected from the group consisting of —C(O)R¹⁵ and —SO₂R¹⁵;

[0043] R⁹ and R¹⁰ are each independently selected from the groupconsisting of: H, F, —CF₃, —CHF₂, alkyl, cycloalkyl, arylalkyl,heteroalkyl, heteroarylalkyl, heterocycloalkyl, hydroxy, alkoxy,aryloxy, —NR¹¹R¹² and —N(R¹¹)C(O)R¹³, provided that when Z is N, then R⁹and R¹⁰ are each not F, hydroxy, alkoxy, aryloxy, —NR¹¹R¹² or—N(R¹¹)C(O)R¹³;

[0044] R¹¹ is selected from the group consisting of H, alkyl, aryl andheteroaryl;

[0045] R¹² is selected from the group consisting of H, alkyl, aryl andheteroaryl;

[0046] R¹³ is selected from the group consisting of alkyl, alkoxy andaryloxy;

[0047] R¹⁴ is selected from the group consisting of H, alkyl, aryl andheteroaryl;

[0048] R¹⁵ is selected from the group consisting of: —NR¹⁶R¹⁷, —OR¹⁶,alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl andheteroarylalkyl, each optionally substituted with R¹⁸;

[0049] R¹⁶ and R¹⁷ are each independently selected from the groupconsisting of: alkyl, aryl, arylalkyl, heteroalkyl and heteroaryl, eachoptionally substituted with R¹⁸, and H, provided that when R¹⁵ is —OR¹⁶,then R¹⁶ is not H;

[0050] R¹⁸ is one to four substituents each independently selected fromthe group consisting of: lower alkyl, halo, cyano, nitro, haloalkyl,hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino,alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl;

[0051] X and Z are each independently selected from the group consistingof C and N; and

[0052] n is 1-4.

[0053] Compounds represented by formula (I) are useful for the treatmentor prevention of androgen dependent diseases, including, but not limitedto, prostate cancer, benign prostatic hyperplasia and prostaticintraepithelial neoplasia. Another aspect of the invention comprises apharmaceutical composition comprising a compound of formula (I), aloneor with another active agent, and a pharmaceutically acceptable carrieror excipient therefore. The inventive compounds and compositions can beused alone or in combination with other active agents and/or methods oftreatment for treating androgen dependent diseases.

[0054] A further understanding of the invention will be had from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] Unless where indicated otherwise, the following definitions applythroughout the present specification and claims. These definitions applyregardless of whether a term is used by itself or in combination withother terms. Hence the definition of “alkyl” applies to “alkyl” as wellas to the “alkyl” portions of “alkoxy”, etc.

[0056] Unless otherwise known, stated or shown to be to the contrary,the point of attachment for a multiple term substituent (multiple termsthat are combined to identify a single moiety) to a subject structure isthrough the last named term of the multiple term. For example, acycloalkylalkyl substituent attaches to a targeted through the latter“alkyl” portion of the substituent (e.g., Structure-alkyl-cycloalkyl).

[0057] When any variable occurs more than one time in any constituent(e.g., R₂), its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

[0058] Unless stated, shown or otherwise known to be the contrary, allatoms illustrated in chemical formulas for covalent compounds possessnormal valencies. Thus, hydrogen atoms, double bonds, triple bonds andring structures need not be expressly depicted in a general chemicalformula.

[0059] Double bonds, where appropriate, may be represented by thepresence of parentheses around an atom in a chemical formula. Forexample, a carbonyl functionality, —CO—, may also be represented in achemical formula by —C(O)— or —C(═O)—. Similarly, a double bond betweena sulfur atom and an oxygen atom may be represented in a chemicalformula by —SO—, —S(O)— or —S(═O)—. One skilled in the art will be ableto determine the presence or absence of double (and triple bonds) in acovalently-bonded molecule. For instance, it is readily recognized thata carboxyl functionality may be represented by —COOH, —C(O)OH, —C(═O)OHor —CO₂H.

[0060] The term “substituted,” as used herein, means the replacement ofone or more atoms or radicals, usually hydrogen atoms, in a givenstructure with an atom or radical selected from a specified group. Inthe situations where more than one atom or radical may be replaced witha substituent selected from the same specified group, the substituentsmay be, unless otherwise specified, either the same or different atevery position. Radicals of specified groups, such as alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl groups, independently of ortogether with one another, may be substituents on any of the specifiedgroups, unless otherwise indicated.

[0061] “Alkyl” represents a straight or branched saturated hydrocarbonchain having the designated number of carbon atoms. Preferably thenumber of carbon atoms is 1 to 20, more preferably 1 to 10, mostpreferably the number of carbon atoms is 1 to 6. Where the number ofcarbon atoms is not specified, 1 to 20 carbons are intended.

[0062] The term “lower alkyl” represents a straight or branchedsaturated hydrocarbon chain having 1 to 6 carbons.

[0063] The term “chemically-feasible” is usually applied to a ringstructure present in a compound and means that the ring structure wouldbe expected to be stable by a skilled artisan.

[0064] The term “cycloalkyl” or “cycloalkane,” as used herein, means anunsubstituted or substituted, saturated, stable, non-aromatic,chemically-feasible carbocyclic ring, having, preferably, from three tofifteen carbon atoms, more preferably, from three to eight carbon atoms.The cycloalkyl carbon ring radical is saturated and may be fused, forexample, benzofused, with one to two cycloalkyl, aromatic, heterocyclicor heteroaromatic rings. The cycloalkyl may be attached at anyendocyclic carbon atom that results in a stable structure. Preferredcarbocyclic rings have from five to six carbons. Examples of cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like.

[0065] The term “heterocycloalkyl” refers to a cycloalkyl group whichhas at least one heteroatom.

[0066] The term “halogen” or “Halo” (halogen) is intended to includefluorine, chlorine, bromine or iodine.

[0067] The term “alkoxy,” as used herein, means an oxygen atom bonded toa hydrocarbon chain, such as an alkyl group (—O-alkyl). Representativealkoxy groups include methoxy, ethoxy and isopropoxy groups.

[0068] The term “aryloxy” as used herein, means an oxygen atom bonded toan aryl group (—O-aryl).

[0069] The term “fluoroalkyl” represents a straight or branchedsaturated hydrocarbon chain having the designated number of carbonatoms, substituted with one or more fluorine atoms. Where the number ofcarbon atoms is not specified, 1 to 20 carbons are intended

[0070] “Aryl” refers to a mono- or bicyclic ring system having one ortwo aromatic rings including, but not limited to, phenyl, naphthyl,indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl and thelike. The aryl group can be unsubstituted or substituted with one, two,or three substituents independently selected from lower alkyl, halo,cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl,carboxamide, mercapto, sulfhydryl, amino, alkylamino, dialkylamino,sulfonyl, sulfonamido, aryl and heteroaryl.

[0071] The term “arylalkyl” refers to an aryl group bonded directly to asubject structure through an alkyl group.

[0072] The term “heteroatom,” as used herein, means a nitrogen, sulfur,or oxygen atom. Multiple heteroatoms in the same group may be the sameor different. The term “heteroalkyl” refers to an alkyl group which hasat least one heteroatom.

[0073] The term “heteroalkyl” refers to an alkyl group which has atleast one heteroatom. Representative examples include alcohols,alkoxyalkyls and alkylaminoalkyls.

[0074] The term “heterocycle” or “heterocyclic ring” is defined by allnon-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatomsselected from N, O and S, such as oxirane, oxetane, tetrahydrofuran,tetrahydropyran, pyrrolidine, piperidine, piperazine,tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene,tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone,and the like.

[0075] The term “heterocyclic acidic functional group” is intended toinclude groups such as, pyrrole, imidazole, triazole, tetrazole, and thelike.

[0076] “Heteroaryl” refers to 5- or 10-membered single or benzofusedaromatic rings consisting of 1 to 3 heteroatoms independently selectedfrom the group consisting of —O—, —S, and —N═, provided that the ringsdo not possess adjacent oxygen and/or sulfur atoms. The heteroaryl groupcan be unsubstituted or substituted with one, two, or three substituentsindependently selected from lower alkyl, halo, cyano, nitro, haloalkyl,hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, sulfhydryl, amino,alkylamino and dialkylamino. Representative heteroaryl groups includethiazoyl, thienyl, pyridyl, benzothienyl and quinolyl.

[0077] The term “heteroarylalkyl” refers to a heteroaryl group bondeddirectly to a subject structure through an alkyl group.

[0078] N-oxides can form on a tertiary nitrogen present in an Rsubstituent, or on ═N— in a heteroaryl ring substituent and are includedin the compounds of formula I.

[0079] The term “prodrug,” as used herein, represents compounds that aredrug precursors which, following administration to a patient, releasethe drug in vivo via a chemical or physiological process (e.g., aprodrug on being brought to a physiological pH or through an enzymeaction is converted to the desired drug form). A discussion of prodrugsis provided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of A.C.S. Symposium Series (1987), and in BioreversibleCarriers in Drug Design, E. B. Roche, ed., American PharmaceuticalAssociation and Pergamon Press (1987), each of which is incorporatedherein by reference in its entirety.

[0080] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0081] The phrase “effective amount,” as used herein, means an amount ofa compound or composition which is sufficient enough to significantlyand positively modify the symptoms and/or conditions to be treated(e.g., provide a positive clinical response). The effective amount of anactive ingredient for use in a pharmaceutical composition will vary withthe particular condition being treated, the severity of the condition,the duration of the treatment, the nature of concurrent therapy, theparticular active ingredient(s) being employed, the particularpharmaceutically-acceptable excipient(s)/carrier(s) utilized, and likefactors within the knowledge and expertise of the attending physician.

[0082] As used herein the term “disease” is intended to include anyabnormal physical or mental condition, including disorders, as well asany symptoms which are subject evidence of a disease or disorder.

[0083] The term “compound having the formula I”, and the like as usedherein, represents a compound having a chemical structure encompassed byformula I, and includes any and all isomers (e.g., enantiomers,stereoisomers, diastereomers, rotomers, tautomers) and prodrugs of thecompound. These compounds can be neutral, acidic or alkaline, andfurther include their corresponding pharmaceutically-acceptable salts,solvates, esters, and the like.

[0084] All isomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of compounds according to the invention embraces all thepossible isomers and their mixtures. It very particularly embraces theracemic forms and the isolated optical isomers having the specifiedactivity. The racemic forms can be resolved by physical methods, suchas, for example, fractional crystallization, separation orcrystallization of diastereomeric derivatives or separation by chiralcolumn chromatography. Unless noted otherwise, inventive compoundsdesignated with a 1 or 2 above the formula correspond to the first andsecond isomers, respectively, to elute from a chiral chromatographycolumn during separation from a diastereomeric mixture.

[0085] The following solvents and reagents are referred to herein by theabbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol(MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc);N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroaceticanhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid(MCPBA); triethylamine (Et₃N); diethyl ether (Et₂O); ethyl chloroformate(ClCO₂Et); and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (DEC); t-butoxycarbonyl (BOC); phenyl group (Ph);trimethylsilyl isocyanate (TMSNCO); triethylamine (TEA); diethylamine(DEA); di-tert-butyl dicarbonate (BOC)₂O;acetyl chloride (AcCl);N-methylmorpholine (NMM); N,N′-dicyclohexylcarbodiimide (DCC); andlithium aluminum hydride (LAH).

[0086] As used herein the following terms have the following meaningsunless indicated otherwise:

[0087] “At least one” means “one or more” preferably 1 to 12, morepreferably 1 to 6, most preferably 1, 2 or 3.

[0088] “Antineoplastic agent”—means a chemotherapeutic agent effectiveagainst cancer;

[0089] “Concurrently”—means simultaneously in time; and

[0090] “Sequentially”—means administration of one component of a methodof treatment involving multi-components, followed by administration ofthe other component(s); after administration of one component, thesecond component can be administered substantially immediately after thefirst component, or the second component can be administered after aneffective time period after the administration of the first component;the effective time period is the amount of time given for realization ofmaximum benefit from the administration of the first component.

Chemotherapeutic Agents

[0091] Classes of compounds that can be used as the chemotherapeuticagent (antineoplastic agent) include: alkylating agents,antimetabolites, natural products and their derivatives, hormones andsteroids (including synthetic analogs), and synthetics. Examples ofcompounds within these classes are given below.

[0092] Alkylating agents (including nitrogen mustards, ethyleniminederivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracilmustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, and Temozolomide.

[0093] Antimetabolites (including folic acid antagonists, pyrimidineanalogs, purine analogs and adenosine deaminase inhibitors):Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

[0094] Natural products and their derivatives (including vincaalkaloids, antitumor antibiotics, enzymes, lymphokines andepipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,paclitaxel (paclitaxel is commercially available as Taxol® and isdescribed in more detail below in the subsection entitled “MicrotubuleAffecting Agents”), Mithramycin, Deoxycoformycin, Mitomycin-C,L-Asparaginase, Interferons-α and β (especially IFN-α, Etoposide, andTeniposide.

[0095] Hormonal agents and steroids (including synthetic analogs):17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, goserelin and Zoladex.

[0096] Synthetics (including inorganic complexes such as platinumcoordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11,Anastrazole, Letrazole, Capecitabine, Ralozifine, Droloxifine andHexamethylmelamine.

[0097] Methods for the safe and effective administration of most ofthese chemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 1996edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); thedisclosure of which is incorporated herein by reference thereto.

[0098] Examples of biological agents useful in the methods of thisinvention include, but are not limited to, interferon-α, interferon-βand gene therapy.

Microtubule Affecting Agents

[0099] As used herein, a microtubule affecting agent is a compound thatinterferes with cellular mitosis, i.e., having an anti-mitotic effect,by affecting microtubule formation and/or action. Such agents can be,for instance, microtubule stabilizing agents or agents which disruptmicrotubule formation.

[0100] Microtubule affecting agents useful in the invention are wellknown to those of skill in the art and include, but are not limited toallocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine(NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel(Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265),vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574),epothilone A, epothilone, and discodermolide (see Service, (1996)Science, 274:2009) estramustine, nocodazole, MAP4, and the like.Examples of such agents are also described in the scientific and patentliterature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda(1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) CancerRes. 57:3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez (1997)Mol. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.

[0101] Particularly preferred microtubule affecting agents are compoundswith paclitaxel-like activity. These include, but are not limited topaclitaxel and paclitaxel derivatives (paclitaxel-like compounds) andanalogues. Paclitaxel and its derivatives are available commercially. Inaddition, methods of making paclitaxel and paclitaxel derivatives andanalogues are well known to those of skill in the art (see, e.g., U.S.Pat. Nos. 5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447;5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120;5,468,769; 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and5,296,506).

[0102] More specifically, the term “paclitaxel” as used herein refers tothe drug commercially available as Taxol® (NSC number: 125973). Taxol®inhibits eukaryotic cell replication by enhancing polymerization oftubulin moieties into stabilized microtubule bundles that are unable toreorganize into the proper structures for mitosis. Of the many availablechemotherapeutic drugs, paclitaxel has generated interest because of itsefficacy in clinical trials against drug-refractory tumors, includingovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23,Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J.Natl. Canc. Inst. 82: 1247-1259).

[0103] Additional microtubule affecting agents can be assessed using oneof many such assays known in the art, e.g., a semiautomated assay whichmeasures the tubulin-polymerizing activity of paclitaxel analogs incombination with a cellular assay to measure the potential of thesecompounds to block cells in mitosis (see Lopes (1997) Cancer Chemother.Pharmacol. 41:37-47).

[0104] Generally, activity of a test compound is determined bycontacting a cell with that compound and determining whether or not thecell cycle is disrupted, in particular, through the inhibition of amitotic event. Such inhibition may be mediated by disruption of themitotic apparatus, e.g., disruption of normal spindle formation. Cellsin which mitosis is interrupted may be characterized by alteredmorphology (e.g., microtubule compaction, increased chromosome number,etc.).

[0105] In a preferred embodiment, compounds with possible tubulinpolymerization activity are screened in vitro. The compounds arescreened against cultured WR21 cells (derived from line 69-2 wap-rasmice) for inhibition of proliferation. and/or for altered cellularmorphology, in particular for microtubule compaction. In vivo screeningof positive-testing compounds can then be performed using nude micebearing the WR21 tumor cells. Detailed protocols for this screeningmethod are described by Porter (1995) Lab. Anim. Sci., 45(2):145-150.

[0106] Other methods of screening compounds for desired activity arewell known to those of skill in the art. Typically, these involve assaysfor inhibition of microtubule assembly and/or disassembly. Assays formicrotubule assembly are described, for example, by Gaskin et al. (1974)J. Molec. Biol., 89: 737-758. U.S. Pat. No. 5,569,720 also provides invitro and in vivo assays for compounds with paclitaxel-like activity.

[0107] Methods for the safe and effective administration of theabove-mentioned microtubule affecting agents are known to those skilledin the art. In addition, their administration is described in thestandard literature. For example, the administration of many of thechemotherapeutic agents is described in the “Physicians' Desk Reference”(PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J.07645-1742, USA); the disclosure of which is incorporated herein byreference thereto.

[0108] One aspect of the present invention relates to a pharmaceuticalcomposition comprising a compound of formula (I) in combination orassociation with a pharmaceutically acceptable carrier or diluent.

[0109] Preferably for compounds of the Formula (I),

[0110] R¹ is selected from aryl such as, for example, phenyl andheteroaryl such as, for example, pyridyl, napthyl, imidazolyl,thiazolyl, thienyl, benzothienyl, furanyl, benzofuranyl, quinolinyl,isoquinolinyl, and indolyl, each optionally substituted with one to sixgroups selected from the following:

[0111] a) halogen, e.g. Cl, F, Br, I;

[0112] b) —OCF₃;

[0113] c) —CF₃;

[0114] d) —CN;

[0115] e) (C1-C20)alkyl or R¹⁸—(C1-C20)alkyl;

[0116] f) heteroalkyl, e.g. NHR¹¹ or R¹⁸-heteroalkyl;

[0117] g) aryl or R¹⁸-aryl;

[0118] h) heteroaryl or R¹⁸-heteroaryl;

[0119] i) arylalkyl, e.g. benzyl, or R¹⁸-arylalkyl;

[0120] j) heteroarylalkyl or R¹⁸-heteroarylalkyl;

[0121] k) hydroxy;

[0122] l) alkoxy;

[0123] m) aryloxy;

[0124] n) —SO₂-alkyl;

[0125] o) —NR¹¹R¹²;

[0126] p) —N(R¹¹)C(O)R¹³,

[0127] q) methylenedioxy;

[0128] r) difluoromethylenedioxy;

[0129] s) trifluoroalkoxy, e.g. —O—(C1-C20)alkylCF₃;

[0130] t) —SCH₃; and

[0131] u) —SO₂CF₃;

[0132] R⁴, R⁵, R⁷ and R⁸ are each independently selected from H, alkyl,heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, OR¹⁴, NR¹¹R¹²

[0133]  provided that when Z and/or X is N then R⁴, R⁵, R⁷ and R⁸ arenot OR¹⁴ or NR¹¹R¹²;

[0134] R¹¹ is selected from H and alkyl;

[0135] Z is C; and

[0136] n=1-3

[0137] In a more preferred embodiment, are compounds of the Formula (I)wherein,

[0138] R¹ is selected from aryl and heteroaryl, each optionallysubstituted with one to six groups selected from following:

[0139] a) halogen;

[0140] b) —OCF₃;

[0141] c) —CF₃;

[0142] d). trifluoroalkoxy;

[0143] e) (C1-C6)alkyl or R¹⁸—(C1-C6)alkyl;

[0144] f) heteroalkyl or R¹⁸-heteroalkyl;

[0145] g) aryl or R¹⁸-aryl;

[0146] h) arylalkyl or R¹⁸-arylalkyl;

[0147] i) heteroarylalkyl or R¹⁸-heteroarylakly; and

[0148] j) alkoxy;

[0149] R⁴, R⁵, R⁷ and R⁸ are each independently selected from thefollowing: H, OR¹⁴, NR¹¹R¹², alkyl, aryl, cycloalkyl, arylalkyl,heteroalkyl, heteroarylalkyl, heterocycloalkyl,

[0150]  provided that when Z and/or X is N, then R⁴, R⁵, R⁷ and R⁸ arenot OR¹⁴ or NR¹¹R¹²;

[0151] R¹¹ is selected from H and alkyl;

[0152] Z is C; and

[0153] n=1-3

[0154] Even more preferred are compounds of the Formula (I) wherein,

[0155] R¹ is selected from aryl and heteroaryl, each optionallysubstituted with one to six groups selected from the following:

[0156] a) halogen;

[0157] b) —OCF₃;

[0158] c) —CF₃;

[0159] d) alkoxy;

[0160] e) trifluoroalkoxy; and

[0161] f) (C1-C6)alkyl or R¹⁸—(C1-C6)alkyl;

[0162] R² and R³ are each independently selected from the following: H,alkyl, and heteroalkyl;

[0163] R⁴, R⁵, R⁷ and R⁸ are each independently selected from thefollowing: H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, OR¹⁴, NR¹¹R¹²

[0164]  provided that when Z and/or X is N, then R⁴, R⁵, R⁷ and R⁸ arenot OR¹⁴ or NR¹¹R¹²;

[0165] R¹¹ is selected from H and alkyl;

[0166] Z is C.

[0167] Yet even more preferred are compounds of the Formula (I) wherein,

[0168] R¹ is selected from aryl and heteroaryl, each optionallysubstituted with one to six groups selected from the following:

[0169] a) halogen;

[0170] b) —OCF₃;

[0171] c) —CF₃;

[0172] d) alkoxy; and

[0173] e) trifluoroalkoxy;

[0174] R² is alkyl;

[0175] R³ is H;

[0176] R⁴ and R⁵ are each independently selected from the following: H,(C1-C6)alkyl, heteroalkyl and

[0177] R⁷ is selected from the following: H, NR¹¹R¹², OR¹⁴ and alkyl,provided that when X is N, then R⁷ is not OR¹⁴ or NR¹¹, R¹²;

[0178] R⁸ is selected from the following: H, alkyl, aryl and heteroaryl,which may each be substituted;

[0179] R¹¹ is selected from H and alkyl; and

[0180] Z is C.

[0181] Most preferred are compounds of the Formula (1) wherein,

[0182] R¹ is selected from phenyl and pyridyl, each optionallysubstituted with one to six groups selected from the following:

[0183] a) Br, F or Cl;

[0184] b) —OCF₃;

[0185] c) —CF₃;

[0186] d) methoxy;

[0187] e) ethoxy;

[0188] f) cyclopropylmethoxy; and

[0189] g) —OCH₂CF₃;

[0190] R² is selected from the following: methyl, ethyl, propyl,cyclopropylmethyl and t-butyl;

[0191] R³ is H;

[0192] R⁴ and R⁵ are each independently selected from the following: H,methyl, ethyl, isopropyl, and t-butyl;

[0193] R⁷ is selected from the following: H, OR¹⁴ and alkyl;

[0194] R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹⁴ are each independently selectedfrom H and alkyl;

[0195] R¹³ is alkyl;

[0196] R¹⁵ is selected from the following: NR¹⁶R¹⁷, OR¹⁶ and alkyl;

[0197] R¹⁶ and R¹⁷ are each independently selected from H and alkyl,provided that when R¹⁵ is OR¹⁶, then R¹⁶ is not H; and

[0198] Z is C.

[0199] Illustrative compounds of Formula (I) are shown below in Table A,where the compound numbers S1, S2, etc. are independent of the numberingused in the Example section. TABLE A

S1

S2

S3

S4

S5

S6

S7

S8

S9

S10

S11

S12

S13

S14

S15

S16

S17

S18 and

S19

[0200] Preferred are compounds represented by the following numbers fromTable A above: S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13,S14, S15, S16 and S17.

[0201] More preferred are compounds represented by the following numbersfrom Table A above: S1, S2, S3, S4, S5, S6, S7,S8, S9 and S10.

[0202] Most preferred are compounds represented by the following numbersfrom Table A above: S1, S2, S3, S4, S5 and S6.

[0203] For compounds of the invention having at least one asymmetricalcarbon atom, all isomers, including diastereomers, enantiomers androtational isomers are contemplated as being part of this invention. Theinvention includes d and l isomers in both pure form and in admixture,including racemic mixtures. Isomers can be prepared using conventionaltechniques, or by separating isomers of a compound of formula I.

[0204] Compounds of formula I can exist in unsolvated and solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for purposes of thisinvention.

[0205] A compound of formula I may form pharmaceutically acceptablesalts with organic and inorganic acids or bases. Examples of suitablebases for salt formation include but are not limited to sodiumhydroxide, lithium hydroxide, potassium hydroxide, and calciumhydroxide. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like. Certain compounds will be acidic innature, e.g. those compounds which possess a carboxyl or phenolichydroxyl group. Salts of phenols can be made by heating acidic compoundswith any of the above mentioned bases according to procedures well knownto those skilled in the art. For purposes of the invention aluminum,gold and silver salts of the compounds are also contemplated. Examplesof suitable acids for salt formation are hydrochloric, sulfuric,phosphoric, acetic, citric, malonic, salicylic, malic, fumaric,succinic, ascorbic, maleic, methanesulfonic and other mineral andcarboxylic acids well known to those skilled in the art. The salts areprepared by contacting the free base forms with a sufficient amount ofthe desired acid to produce a salt in the conventional manner. The freebase forms may be regenerated by treating the salt with a suitabledilute aqueous base solution, such as dilute aqueous sodium hydroxide,lithium hydroxide, potassium hydroxide, calcium hydroxide, potassiumcarbonate, ammonia or sodium bicarbonate.

[0206] The present invention provides a method of inhibiting type 317β-hydroxysteroid dehydrogenase in a mammal, e.g. a human, whichcomprises administering to a patient in need thereof of an effectiveamount, i.e. a therapeutically effective amount, of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0207] In another aspect, the present invention provides a method oftreating or preventing androgen or estrogen dependent diseases in amammal, e.g. a human, which comprises administering to a patient in needthereof a therapeutically effective amount of a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof.

[0208] In yet another aspect, the present invention provides a method oftreating or preventing prostate cancer, and other androgen-dependentneoplasms, benign prostatic hyperplasia, prostatic intraepithelialneoplasia, androgenic alopecia (i.e. pattern baldness in both male andfemale patients), hirsutism, polycystic ovary syndrome and acne in amammal, e.g. a human, which comprises administering to a patient in needthereof, a therapeutically effective amount of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof.

[0209] The present invention also provides a method of treating orpreventing androgen-dependent diseases, comprising administering to amammal (e.g. human) in need thereof an effective amount of a compound ofthe invention in combination with at least one anti-androgenic agent(i.e. agents that decrease androgen synthesis or activity).

[0210] Examples of such agents include, but are not limited to, thefollowing: inhibitors of 5α-reductase type 1 and/or type 2, e.g.finasteride, SKF105,657, LY191,704, LY320,236, dutasteride, Flutamide,nicalutamide, bicalutamide, LHRH agonists e.g. leuprolide and zoladex,LHRH antagonists, e.g. abarelix and cetrorelix, inhibitors of17α-hydroxylase/C17-20 lyase, e.g. YM116, CB7630 and liarozole;inhibitors of 17β-Hydroxysteroid dehydrogenase type 5 and/or other17β-Hydroxysteroid dehydrogenase/17β-oxidoreductase isoenzymes, e.g.EM-1404.

[0211] Types of androgen or estrogen dependent diseases include, but arenot limited to, prostate cancer, benign prostatic hyperplasia, prostaticintraepithelial neoplasia, acne, seborrheas, hirsutism, androgenicalopecia, precocious puberty, adrenal hyperplasia, and polycysticovarian syndrome, breast cancer, endometriosis and leiomyoma.

[0212] This invention further provides a method of treating orpreventing benign prostatic hyperplasia, comprising administering aneffective amount of a compound of the invention in combination with atleast one agent useful in the treatment or prevention of benignprostatic hyperplasia. Examples of such agents include, but are notlimited to, alpha-1 adrenergic antagonists, e.g. tamsulosin andterazosin.

[0213] This invention also provides a method of treating or preventinghair loss, comprising administering an effective amount of a compound ofthe invention in combination with at least one anti-alopecia agent (i.e.agents that treat or prevent hair loss). Useful anti-alopecia agentsinclude potassium channel agonists, e.g., minoxidil and KC-516, or5α-reductase inhibitors, e.g., finasteride and dutasteride.

[0214] The present invention also provides a method of treating orpreventing proliferative diseases, especially cancers (tumors),comprising administering concurrently or sequentially, (1) an effectiveamount (e.g., a therapeutically effective amount) of a compound of theinvention, described herein, to a mammal (e.g., a human) in need of suchtreatment in combination with (2) an effective amount of an anti-canceragent, i.e., a chemotherapeutic agent, biological agent, and/or surgery,(e.g., prostatectomy) and/or radiation therapy (preferably,γ-radiation).

[0215] Examples of cancers (i.e. tumors) which may be inhibited ortreated with a compound of this invention, alone or in combination withan anti-cancer agent, include, but are not limited to, lung cancer(e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreaticcarcinoma such as, for example, exocrine pancreatic carcinoma), coloncancers (e.g., colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), renal cancers, myeloid leukemias (forexample, acute myelogenous leukemia (AML), thyroid follicular cancer,myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma,melanoma, breast cancer and prostate cancer.

[0216] The method of treating proliferative diseases (cancer), accordingto this invention, includes a method for treating (inhibiting) theabnormal growth of cells, including transformed cells, in a patient inneed of such treatment (e.g., a mammal such as a human), byadministering, concurrently or sequentially, an effective amount of acompound of this invention and an effective amount of an anti-canceragent. Abnormal growth of cells means cell growth independent of normalregulatory mechanisms (e.g., contact inhibition or apoptosis), includingthe abnormal growth of: (1) tumor cells (tumors) expressing an activatedras oncogene; (2) tumor cells in which the ras protein is activated as aresult of oncogenic mutation in another gene; and (3) benign andmalignant cells of other proliferative diseases.

[0217] In preferred embodiments, the methods of the present inventioninclude methods for treating or inhibiting tumor growth in a patient inneed of such treatment (e.g., a mammal such as a human) byadministering, concurrently or sequentially, (1) an effective amount ofa compound of this invention and (2) an effective amount of anantineoplastic/microtubule agent; biological agent, and/or surgery (e.g.prostatectomy) and/or radiation therapy. Examples of tumors which may betreated include, but are not limited to, epithelial cancers, e.g.,prostate cancer, lung cancer (e.g., lung adenocarcinoma), pancreaticcancers (e.g., pancreatic carcinoma such as, for example, exocrinepancreatic carcinoma), breast cancers, renal cancers, colon cancers(e.g., colorectal carcinomas, such as, for example, colon adenocarcinomaand colon adenoma), ovarian cancer, and bladder carcinoma. Other cancersthat can be treated include melanoma, myeloid leukemias (for example,acute myelogenous leukemia), sarcomas, thyroid follicular cancer, andmyelodysplastic syndrome.

Biological Data

[0218] 17β-hydroxysteroid Dehydrogenase Inhibition Data Methods:

[0219] To prepare human recombinant type 3 17β-hydroxysteroiddehydrogenase enzyme, HEK-293 cells stably transfected with human17β-HSD type 3 were cultured to confluency and harvested for enzyme. Thecells were suspended in isolation buffer (20 mM KH₂PO₄, 1 mM EDTA, 0.25M Sucrose, 1 mM PMSF, 5 μg/ml pepstatin A, 5 μg/ml antipain and 5 μg/mlleupeptin) to a concentration between 5.0×10⁶ and 1.0×10⁷ cells/ml. Thecells were sonicated on ice using a micro-ultrasonic cell disrupter atan output setting of No. 40 for four 10 second bursts. The broken cellswere then centrifuged at 100,000×g for 60 min at 4° C., and theresulting pellet was resuspended, aliquoted into microfuge tubes, andstored at −80° C.

[0220] To measure conversion of ¹⁴C-androstenedione to ¹⁴C-testosterone,reaction buffer (12.5 mM KH₂PO₄, 1 mM EDTA), NADPH cofactor (1 mMfinal), test compound, 17β-HSD3 enzyme (30 μg protein) and¹⁴C-androstenedione substrate (100 nM; 2.7 nCi/tube) were added to13×100 borosilicate glass tubes to a total volume of 0.5 mL/tube. Thetubes were placed in a prewarmed 37° C. water bath for 30 minutes. Thereaction was then stopped by adding 1 ml of ethyl ether. The tubes werecentrifuged for 20 minutes at 3000 rpm at 4° C. in a table topcentrifuge and then snap frozen in a dry ice-methanol bath. The etherlayer was decanted into another glass tube, and then evaporated todryness using compressed nitrogen gas. The samples were resuspended inchloroform (20 mL) and spotted onto silica G60 thin layer chromatographyplates. ¹⁴C-Androstenedione substrate and ¹⁴C-testosterone product wereseparated by placing the plates in chloroform:ethyl acetate (3:1). Theplates were dried, exposed overnight, scanned and quantitated on a FUJIFLA2000 phosphorimager.

[0221] The percent inhibition of 17β-HSD3 activity is the differencebetween the percent of maximum specific binding (“MSB”) and 100%. Thepercent of MSB is defined by the following equation, wherein “dpm”represents “disintegrations per minute”:${\% \quad {MSB}} = {\frac{\left( {{dpm}\quad {of}\quad {unknown}} \right) - \left( {{dpm}\quad {of}\quad {nonspecific}\quad {binding}} \right)}{\left( {{dpm}\quad {of}\quad {total}\quad {binding}} \right) - \left( {{dpm}\quad {of}\quad {nonspecific}\quad {binding}} \right)} \times 100}$

[0222] The concentration at which a compound having formula I produces50% inhibition of binding is then used to determine an inhibitionconstant (“Ki”) using the Chang-Prusoff equation.

[0223] It will be recognized that the compounds having formula I caninhibit 17β-HSD3 to varying degrees. The compounds useful for practiceof the invention exhibit potent affinities to bind 17β-HSD3 as measuredby Ki values (in nM). The activities (potencies) for these compounds aredetermined by measuring their Ki values. The smaller the Ki value, themore active is a compound for inhibiting a particular enzyme.

[0224] Compounds of this invention have a range of 17B-Hydroxysteroiddehydrogenase Type 3 binding activity from about 0.010 nM to about >100nM. Preferably compounds of this invention have a binding activity inthe range of about 0.010 nM to 100 nM, more preferably about 0.010 to 50nM, and most preferably about 0.010 nM to 10 nM.

[0225] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

[0226] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0227] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0228] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0229] The compounds of the invention may also be deliverabletransdermally. The transdermal composition can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0230] Preferably the compound is administered orally.

[0231] Preferably; the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0232] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 0.01 mg to about 1000 mg, preferablyfrom about 0.01 mg to about 750 mg, more preferably from about 0.01 mgto about 500 mg, and most preferably from about 0.01 mg to about 250 mg,according to the particular application.

[0233] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage regimen for a particularsituation is within the skill of the art. For convenience, the totaldosage may be divided and administered in portions during the day asrequired.

[0234] The amount and frequency of administration of the compounds offormula (I) will be regulated according to the judgment of the attendingclinician (physician) considering such factors as age, condition andsize of the patient as well as severity of the disease being treated. Adosage regimen of the compound of formula (I) can be oral administrationof from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, morepreferably 50 to 600 mg/day, in two to four (preferably two) divideddoses. Intermittent therapy (e.g., one week out of three weeks or threeout of four weeks) may also be used.

[0235] The chemotherapeutic agent and/or radiation therapy can beadministered in association with the compounds of the present inventionaccording to the dosage and administration schedule listed in theproduct information sheet of the approved agents, in the Physicians DeskReference (PDR) as well as therapeutic protocols well known in the art.Table 1.0 below gives ranges of dosage and dosage regimens of someexemplary chemotherapeutic agents useful in the methods of the presentinvention. It will be apparent to those skilled in the art that theadministration of the chemotherapeutic agent and/or radiation therapycan be varied depending on the disease being treated and the knowneffects of the chemotherapeutic agent and/or radiation therapy on thatdisease. Also, in accordance with the knowledge of the skilledclinician, the therapeutic protocols (e.g., dosage amounts and times ofadministration) can be varied in view of the observed effects of theadministered chemotherapeutic agents (i.e., antineoplastic agent orradiation) on the patient, and in view of the observed responses of thedisease to the administered therapeutic agents. TABLE 1.0 ExemplaryChemotherapeutic Agents Dosage and Dosage Regimens Cisplatin: 50-100mg/m² every 4 weeks (IV)* Carboplatin: 300-360 mg/m² every 4 weeks (IV)Taxotere: 60-100 mg/m² every 3 weeks (IV) Gemcitabine: 750-1350 mg/m2every 3 weeks (IV) Taxol: 65-175 mg/m2 every 3 weeks (IV)

[0236] Anti-androgenic agents, anti-benign prostatic hyperplasia agents,potassium channel agonists and biological agents can be administered inassociation with the compounds of the present invention according to thedosage and administration schedule listed in the product informationsheet of the approved agents, in the Physicians Desk Reference (PDR) aswell as therapeutic protocols well known in the art. It will be apparentto those skilled in the art that the administration of the agents can bevaried depending on the disease being treated and the known effects ofthe agents on that disease. Also, in accordance with the knowledge ofthe skilled clinician, the therapeutic protocols (e.g., dosage amountsand times of administration) can be varied in view of the observedeffects of the administered agents on the patient, and in view of theobserved responses of the disease to the administered therapeuticagents.

[0237] Compounds of formula (I) may be produced by processes known tothose skilled in the art in the following reaction schemes and in thepreparations and examples below.

[0238] As shown in Scheme 1 above, the piperazine-piperidine core isadded to an appropriate chloride. Deprotection and acylation gives thedesired product.

[0239] Alternatively, for those more sterically encumbered piperazines,direct coupling is successful in giving the regiochemically desiredproduct (see Scheme 2 above).

[0240] The regiochemical analogs can be prepared through the sequentialmodification of protecting groups in accordance with Scheme 3 above.

[0241] The reductive amination of piperazine-piperidine core, followedby deprotection and acylation, gives the desired product as shown inScheme 4 above.

[0242] The synthesis of desired chlorides can be accomplished by theaddition of an appropriate organometallic to an appropriate aldehyde orketone (see Scheme 5 above). The resulting alcohol is then converted tothe requisite chloride under standard conditions.

[0243] Alternatively, the synthesis of desired chlorides can beaccomplished by the reduction of an appropriate ketone, as shown inScheme 6 above. The resulting alcohol is then converted to the requisitechloride under standard conditions.

[0244] The synthesis of desired ketone can be accomplished by theaddition of an appropriate organometallic to the N, O-dimethylamide,which is converted from an appropriate acid under standard conditions(see Scheme 7 above).

[0245] The substituted piperazines can be prepared through the reductionof commercially available diketopiperazines or alternatively from thedesired amino acids, as shown in Scheme 8 above.

[0246] The N-BOC or N-acyl piperidine acetic acid can be prepared asdescribed previously through the reduction of 4-pyridine acetic acid(see Scheme 9 above).

[0247] The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

Preparative Example 1

[0248]

[0249] To a solution of DCC (43.2 mL, 1.0 M in CH₂Cl₂, 1.0 eq.) inCH₂Cl₂ (200 mL) at 0° C. was added N-t-BOC-L-leucine (10 g, 43.2 mmol).To the resulting slurry was added ethyl N-benzylglycinate (8.1 mL, 1.0eq.) over 15 minutes. The resulting solution was stirred at 0° C. for 2hours and room temperature for 1 hour, filtered and then concentrated togive an oil (20.7 g, LCMS: MH⁺=407). The intermediate was dissolved inCH₂Cl₂ (150 mL) through which HCl (g) was bubbled for 4 hours. Thesolution was purged with N₂ and concentrated under reduced pressure. Theresidue was neutralized with saturated NaHCO₃ and extracted with EtOAc(3×200 mL). The combined organics were washed with water, dried overNa₂SO₄, filtered and concentrated to give a solid which was used withoutfurther purification (11.3 g, 100% yield). LCMS: MH⁺=261.

Preparative Example 2-4

[0250] By essentially the same procedure set forth in PreparativeExample 1 substituting the amino acids from Table 1, Column 2, the titlecompounds in Table 1, Column 3, were prepared: TABLE 1 Prep. Ex. Column2 Column 3 Phys. data 2

LCMS: MH⁺ = 261 3

LCMS: MH⁺ = 261 4

—

Preparative Example 5

[0251]

[0252] To a solution of (S)-3-isopropyl-2,5-piperazinedione (5.0 g, 32mmol) in THF (100 ml) at 0° C. was added LAH (137 mL, 1.0 M in THF, 4.3eq.) dropwise. After the addition was complete, the resulting solutionwas heated to reflux overnight. The reaction mixture was cooled to roomtemperature and quenched by the slow, sequential addition of water (5.23mL), 1N NaOH (5.23 mL), and water (5.23 mL). The resulting slurry wasdiluted with EtOAc and filtered through a plug of Celite. The residuewas washed with EtOAC (4×100 mL) and the combined organics concentratedunder reduced pressure. The crude product was purified by flashchromatography using a gradient of 5% MeOH, 10% MeOH, 5% (10% NH₄OH) inMeOH, 10% (10% NH₄OH) in MeOH, and 20% (10% NH₄OH) in MeOH in CH₂Cl₂ togive a solid (3.03 g, 74% yield). LCMS: MH⁺=129.

Preparative Examples 6-9

[0253] By essentially the same procedure set forth in PreparativeExample 5 substituting the piperazinediones (column 2) from PreparativeExamples 1-4, the compounds in column 3 were prepared: TABLE 2 Prep. Ex.Column 2 Column 3 Phys. data 6

LCMS: MH⁺ = 233 7

LCMS: MH⁺ = 233 8

LCMS: MH⁺ = 233 9

FABMS: MH⁺ =235

Preparative Example 10

[0254]

[0255] To a solution of N-Boc-4-piperidineacetic acid (prepared asdescribed in U.S. Pat. No. 5,874,442; 35.0 g, 144 mmol) and TEA (20.0mL, 1.0 eq.) in toluene (100 mL) at 0° C. was added trimethylacetylchloride (17.7 mL, 1.0 eq.). The resulting slurry was stirred at 0° C.for 1.5 hours before adding the product from Preparative Example 9 (33.5g, 151 mmol, 1.05 eq.) in toluene (100 mL) and the resulting solutionwas warmed to room temperature and stirred overnight. The reactionmixture was neutralized by the addition of 1N NaOH and extracted withEtOAc. The combined organics were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatographyusing a 50:50 EtOAc:Hexanes solution as eluent (34.4 g, 51% yield).LCMS: MH⁺=458.

Preparative Example 11

[0256]

[0257] To a solution of the product from Preparative Example 10 (34.0 g,74.3 mmol) in absolute EtOH (600 mL) was added 10% Pd—C (35.0 g, wet,50%) and NH₄HCO₂ (94 g, 10 eq.). The reaction mixture was heated toreflux for 3 hours, cooled to room temperature, filtered through a plugof Celite and concentrated under reduced pressure. The residue wasdiluted with EtOAc and washed sequentially with H₂O, 1N NaOH, H₂O, andbrine. The organics were dried over Na₂SO₄, filtered, and concentratedin vacuo. The crude product was purified by flash chromatography using a5% (10% NH₄OH in MeOH) in CH₂Cl₂ to 10% (10% NH₄OH in MeOH in CH₂Cl₂ aseluent (20 g, 74% yield). LCMS: MH⁺=368.

Preparative Example 12

[0258]

[0259] To a solution of the product from Preparative Example 7 (8.2 g,31.5 mmol) in CH₂Cl₂ (300 mL) was added (BOC)₂O (7.5 g, 1.02 eq.). Theresulting solution was stirred at room temperature overnight. Thereaction was quenched by the addition of saturated NaHCO₃ and separated.The organic layer was washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The crude product was purifiedby flash chromatography using a 10% EtOAc in hexanes solution as eluent(10.6 g, 99% yield). LCMS: MH⁺=333.

Preparative Example 13

[0260]

[0261] By essentially the same procedure set forth in PreparativeExample 12, only substituting the product from Preparative Example 10,the above compound was prepared. LCMS: MH⁺=335.

Preparative Example 14

[0262]

[0263] By essentially the same procedure set forth in PreparativeExample 11 only substituting the product from Preparative Example 13,the above compound was prepared.

Preparative Example 15

[0264]

[0265] A solution of Mg (1.16 g, 1.6 eq.) and I₂ (cat.) in Et₂O (48 mL)was treated with 3,3,3-trifluoro-1-iodopropane (8.0 g, 1.2 eq. initially20% of total) and the resulting solution was heated to reflux toinitiate Grignard formation. Following initiation, the remaining3,3,3-trifluoro-1-iodopropane was added dropwise to maintain a gentlereflux. The reaction mixture was stirred at room temperature anadditional hour and transferred via canulae to a solution of4-trifluorobenzaldehyde (4.1 mL, 30 mmol) in Et₂O (95 mL) at 0° C. Theresulting solution was stirred at 0° C. for 1 hour and room temperaturefor 1 hour. The reaction was quenched by pouring it over ice (100 g) andsaturated NH₄Cl. The resulting solution was extracted with CH₂Cl₂, thecombined organics were dried over Na₂SO₄, filtered, concentrated andused without further purification.

Preparative Example 16-18

[0266] By essentially the same procedure set forth in PreparativeExample 15 only substituting the commercial available alkyl magnesiumhalides in Table 3, column 2 and the arylaldehydes in column 3, thecompounds in column 4 were prepared: TABLE 3 Prep Ex. Column 2 Column 3Column 4 16

CH₃MgCl

17

(CH₃)₂CHMgCl

18

BuMgCl

Preparative Example 19

[0267]

[0268] To a solution of 1,2-dichloro-4-iodobenzene (1.0 g, 3.68 mmol) inether (10 mL) at 0° C. was added iPrMgCl (2.2 mL, 2M in Et₂O) dropwiseand the resulting solution stirred at 0° C. for 30 minutes and roomtemperature 1 hour. The reaction mixture was recooled to 0° C. andcyclopropylacetonitrile (0.34 mL, 1.0 eq.) was added. The reactionmixture was stirred at 0° C., room temperature 1 hour, then quenched bythe addition of 1N HCl. The resulting solution was stirred at roomtemperature 2 hours and extracted with CH₂Cl₂. The combined organicswere dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by flash chromatography using a 100% hexanes to 10% EtOAcin hexanes solution gradient as eluent (0.10 g, 21% yield). LCMS:MH⁺=227.

Preparative Example 20

[0269]

[0270] The product from Preparative Example 19 (0.45 g, 1.97 mmol) inTHF (5.0 mL) and MeOH (1.0 mL) was stirred at 0° C. with NaBH₄ (0.075 g,1.0 eq.) for 1 hour. The resulting solution was quenched by the additionof water and extracted with CH₂Cl₂. The combined organics were driedover Na₂SO₄, filtered, concentrated under reduced pressure and usedwithout further purification.

Preparative Example 21

[0271]

[0272] To the product from Preparative Example 16 (1.57 g, 10 mmol) intoluene (5.0 mL) at 0° C. was added SOCl₂ (2.39 g, 2.0 eq.) dropwise.The resulting solution was stirred at 0° C. for 1 hour, warmed to roomtemperature and stirred overnight. The crude reaction mixture wasconcentrated under reduced pressure to give the above compound which wasused without further purification.

Preparative Examples 22-23

[0273] By essentially the same procedure as set forth in PreparativeExample 21, the compounds in Table 4, Column 3 were prepared from thecorresponding alcohols in Column 2. TABLE 4 Prep. Ex. Column 2 Column 322

23

Preparative Example 24

[0274]

[0275] To a solution of the product from Preparative Example 20 (0.48 g,2.08 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added Et₃N (0.87 mL, 3 eq.),followed by methanesulfonyl chloride (0.306 mL, 1.5 eq.). The reactionmixture was stirred at 0° C. for 1 hour, then quenched by the additionof saturated NaHCO₃. The resulting solution was extracted with CH₂Cl₂.The combined organics were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatographyusing a 40:60 EtOAc:Hexanes solution as eluent (0.47 g, 73% yield).

Preparative Example 25

[0276]

[0277] By essentially the same procedure set forth in PreparativeExample 24 only substituting the product from Preparative Example 15,the above compound was prepared (0.36 g, 82% yield).

Preparative Example 26

[0278]

[0279] To a solution of the product from Preparative Example 14 (0.25 g,1.0 mmol) and 3,4-dichlorobenzaldehyde (0.23 g, 1.3 eq.) in CH₂Cl₂ (5mL) was added NaHB (OAc)₃ (0.32 g, 1.5 eq.) and AcOH (0.14 mL, 2.4 eq.)and the resulting solution was stirred at room temperature for 96 hours.The reaction mixture was quenched by the addition of saturated NaHCO₃and extracted with CH₂Cl₂. The combined organics were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by flash chromatography using a 10% EtOAc in CH₂Cl₂ solution aseluent (0.27 g, 66% yield). FABMS: MH⁺=403.

Preparative Example 27

[0280]

[0281] By essentially the same procedure set forth in PreparativeExample 26 only substituting the product from Preparative Example 11,the above compound was prepared (0.33 g, 92% yield). LCMS: MH⁺=526.

Preparative Examples 28-30

[0282] By essentially the same procedure as set forth in PreparativeExample 27, the compounds in Table 5, Column 3 were prepared from thecorresponding aldehydes in Column 2: TABLE 5 Prep. Ex. Column 2 Column 3CMPD 28

LCMS: MH⁺ = 536 29

— 30

LCMS: MH⁺ = 548

Preparative Example 31

[0283]

[0284] To a solution of the product from Preparative Example 28 (0.26 g,0.485 mmol), 3,4-dichlorophenyl boronic acid (0.19 g, 2.0 eq.) andNa₂CO₃ (0.15 g, 2.0 eq.) in THF:H₂O (4:1, 10 mL) was added PdCl₂(PPh₃)₂(0.034 g, 10 mol %). The resulting solution was heated to refluxovernight. The reaction mixture was cooled to room temperature, quenchedby the addition of H₂O, and extracted with CH₂Cl₂. The combined organicswere dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by flash chromatography using a 10:90 EtOAc:CH₂Cl₂ solutionas eluent to yield the product (0.17 g, 58% yield). LCMS: MH⁺=602.

Preparative Examples 32

[0285]

[0286] By essentially the same procedure set forth in PreparativeExample 31, only substituting the product from Preparative Example 29(0.25 g, 0.465 mmol) the above compound (0.12 g, 43% yield) wasprepared. LCMS: MH⁺=603.

Preparative Examples 33

[0287]

[0288] The product from Preparative Example 26 (0.26 g, 0.48 mmol) wasstirred at room temperature in TFA (5 mL) for 1 hour. The resultingsolution was concentrated under reduced pressure and used withoutfurther purification.

Preparative Example 34

[0289]

[0290] A solution of benzhydryl chloride (5.40 g, 26.6 mmol), theproduct from Preparative Example 5 (3.4 g, 26.6 mmol) and NaI (0.75 g, 5mmol) in CH₃CN (40 mL) was heated to reflux overnight. The reactionmixture was cooled to room temperature, quenched by the addition ofsaturated NaHCO₃, and extracted with CH₂Cl₂. The combined organics weredried over Na₂SO₄, filtered, and concentrated. The crude product waspurified by flash chromatography using a 5% MeOH (10% NH₄OH) in CH₂Cl₂to yield a solid (4.02 g, 51% yield). LCMS: MH⁺=295.

Preparative Example 35

[0291]

[0292] The product from Preparative Example 34(4.00 g, 13.6 mmol),N-Boc-4-piperadineacetic acid (3.30 g, 13.6 mmol), DEC (3.39 g, 1.3eq.), HOBt (2.43 g, 1.3 eq.), and NMM (3.54 g, 2.5 eq.) were stirred atroom temperature CH₂Cl₂ for 1.5 days. The reaction mixture was pouredinto saturated NaHCO₃ and extracted with CH₂Cl₂. The combined organicswere dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by flash chromatography using a 5% MeOH (10% NH₄OH) inCH₂Cl₂ to yield a solid (6.7 g, 96% yield). LCMS: MH⁺=520.

Preparative Example 36

[0293]

[0294] TFA (4.0 mL) was added to a solution of the product fromPreparative Example 35 (2.00 g, 3.86 mmol) in anhydrous CH₂Cl₂ (40 mL)at 0° C. under N₂. The mixture was stirred at 0° C. for 15 min, then 16mL of TFA was added and the stirring was continued for another 30 min at0° C. The mixture was poured onto solid K₂CO₃ (50 g), H₂O (200 mL) wasadded, and the mixture was extracted with CH₂Cl₂ (4×30 mL). The extractswere dried over Na₂SO₄, filtered, and the solvent was evaporated. Thesolid was dissolved in anhydrous CH₂Cl₂ (30 mL), and Ac₂O (0.79 g, 7.7mmol) and TEA (1.95 g, 19.3 mmol) were added. The mixture was stirredunder N₂ for 24 hrs, poured into sat. NaHCO₃ (50 mL), and extracted withCH₂Cl₂ (2×30 mL). The combined extracts were dried over Na₂SO₄ andfiltered. The residue was purified by flash chromatography using 7% MeOH(10% NH₄OH) in CH₂Cl₂ to give a solid (1.63 g; 92%) LCMS: MH⁺=462;mp=65-71° C.

Preparative Example 37

[0295]

[0296] TFA (4.0 mL) was added to a solution of the product fromPreparative Example 35 (2.00 g, 3.86 mmol) in anhydrous CH₂Cl₂ (40 mL)at 0° C. under N₂. The mixture was stirred at 0° C. for 15 min, then 16mL of TFA was added and the stirring was continued for another 30 min at0° C. The mixture was poured onto solid K₂CO₃ (50 g), H₂O (200 mL) wasadded and the mixture was extracted with CH₂Cl₂ (4×30 mL). The extractswere dried over Na₂SO₄, filtered, and the solvent was evaporated. Thesolid was dissolved in anhydrous CH₂Cl₂ (30 mL), and TEA (1.95 g, 19.3mmol) and TMSNCO (4.44 g, 38.6 mmol) were added. The mixture was stirredunder N₂ for 3 hrs, poured into sat. NaHCO₃ (200 mL), and extracted withCH₂Cl₂ (2×30 mL). The combined extracts were dried over Na₂SO₄,filtered, and the solvent was evaporated. The residue was purified byflash chromatography using 11% MeOH (10% NH₄OH) in CH₂Cl₂ to give asolid (1.51 g; 85%). LCMS: MH⁺=463; mp =100-107° C.

Preparative Example 38

[0297]

[0298] A solution of the product from Example 36 (1.00 g, 2.20 mmol) andHCO₂NH₄ (2.77 g, 44.0 mmol) in anhydrous MeOH (30 mL) was added under N₂to a suspension of 10% Pd/C (1.17 g) in anhydrous MeOH (20 mL). Themixture was stirred for 16 hrs under N₂, poured into 250 CH₂Cl₂ (250mL), and filtered through Celite. The solvent was evaporated and theresidue was purified by flash chromatography using 11% MeOH (10% NH₄OH)in CH₂Cl₂ to give 555 mg (87%) of a solid.

Preparative Example 39

[0299]

[0300] By essentially the same procedure given in Preparative Example38, 1.00 g (2.20 mmol) of the product from Preparative Example 37 wasconverted into 520 mg (81%) of the above compound as a solid.

Preparative Example 40

[0301]

[0302] By essentially the same procedure given in Preparative Example38, the product from Preparative Example 35 was converted into 4.02 g(91%) of the above compound as a wax.

Preparative Example 41

[0303]

[0304] A solution of the product from Preparative Example 22 (0.071 g,0.35 mmol), the product from Preparative Example 40 (0.1 g, 0.28 mmol),NaI (0.045 g, 0.3 mmol) and K₂CO₃ (0.15 g, 1.1 mmol) in CH₃CN (3 mL) washeated to reflux for 2.5 days. The reaction mixture was cooled to roomtemperature, quenched by the addition of 5% K₂CO₃, and extracted withCH₂Cl₂. The combined organics were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatographyusing a 3% MeOH (10% NH₄OH) in CH₂Cl₂ to give a solid (0.029 g, 20%yield). LCMS: MH⁺=521.

Preparative Example 42

[0305]

[0306] A solution of the products from Preparative Example 11 (0.977 g,1.75 eq.) and Preparative Example 24 (0.47 g, 1.52 mmol), K₂CO₃ (0.525g, 2.5 eq.), and KI (0.228 g, 1.0 eq.) in CH₃CN (20 mL) was heated toreflux for 24 hours. The reaction mixture was cooled, diluted withsaturated NaHCO₃, and extracted with EtOAc. The combined organics weredried over Na₂SO₄, filtered, and concentrated. The crude product waspurified by flash chromatography using a 50:50 Hexanes:EtOAc solution aseluent (0.45 g, 51% yield). LCMS: MH⁺=580.

Preparative Examples 43 and 44

[0307]

[0308] The above compounds were prepared by the separation ofdiastereomers of the product from Preparative Example 42 by preparativeHPLC, using a CHIRALPAK AD column with 98:2 hexanes:IPA with 0.2% DEA aseluent:

[0309] Preparative Example 43 (first eluting isomer): LCMS: MH⁺=580.

[0310] Preparative Example 44 (second eluting isomer): LCMS: MH⁺=580.

Preparative Example 45

[0311]

[0312] By essentially the same procedure set forth in PreparativeExample 42 only substituting the product from Preparative Example 25,the above compound was prepared (0.3 g, 32% yield) LCMS: MH⁺=622.

Preparative Example 46

[0313]

[0314] A solution of the product from Preparative Example 42 (0.15 g,0.26 mmol) in 4 M HCl in dioxane (5 mL) was stirred at room temperaturefor 2 hours. The resulting solution was concentrated under reducedpressure. The residue was dissolved in CH₂Cl₂, neutralized by theaddition of 1N NaOH and separated. The organics were dried over Na₂SO₄,filtered and concentrated to give a solid (0.12 g, 96% yield) which wasused without further purification LCMS: MH⁺=480.

Preparative Examples 47-54

[0315] By essentially the same procedure set forth in PreparativeExample 46, only substituting the compounds in Table 7, column 2, thecompounds in column 3 were prepared (CMPD). TABLE 7 Prep. Ex. Column 2Column 3 CMPD 47

— 48

— 49

LCMS: MH⁺ = 502 50

LCMS: MH⁺ = 503 51

— 52

LCMS: MH⁺ = 480 53

LCMS: MH⁺ = 480 54

—

Preparative Example 55

[0316] Step A:

[0317] To a solution of piperidine-4-acetic acid (10.0 g, 70.0 mmol) inEtOH (100 mL) was added concentrated HCl (2.68 mL, 2.2 eq.). Theresulting solution was heated at reflux for 12 hours. The reactionmixture was concentrated under reduced pressure and used without furtherpurification (10 g, 84% yield).

[0318] Step B:

[0319] To a solution of the product from Step A above, (2.0 g, 9.6 mmol)in CH₂Cl₂ (30 mL) at 0° C. was added TMSNCO (6.3 mL, 5.0 eq.) followedby TEA (2.0 mL, 1.5 eq.). The resulting solution was stirred at 0° C.for 3 hours, quenched with water and diluted with saturated NaHCO₃. Themixture was extracted with CH₂Cl₂. The combined organics were dried overNa₂SO₄, filtered, and concentrated. The crude product was purified byflash chromatography using an 8% (10% NH₄OH in MeOH) in CH₂Cl₂ as eluent(1.2 g, 60% yield) FABMS: MH⁺=215.

[0320] Step C:

[0321] A solution of the product from Step B above, (1.23 g, 5.7 mmol)and LiOH (0.33 g, 2.4 eq.) in CH₂Cl₂ (29 mL), EtOH (29 mL) and water (14mL) was heated at reflux for 3 hours. The resulting solution was cooledto room temperature, neutralized by the addition of 1N HCl (16.1 mL,2.98 eq.) and concentrated under reduced pressure. The reaction productwas further dried by the azeotropic removal of water with toluene toyield a gum (1.1 g, quantitative yield). FABMS: MH⁺=187.

EXAMPLES Examples 100-102

[0322] By essentially the same procedure set forth in PreparativeExample 41 only using the chlorides in column 2 of Table 6, and thepiperazines in Column 3, the products in Column 4, were prepared. TABLE6 Ex. Column 2 Column 3 Column 4 CMPD 100

LCMS: MH⁺ = 434. 101

LCMS: MH⁺ '2 435 mp =76-82° C. 102

LCMS: MH⁺ = 462.

Example 103

[0323]

[0324] To a solution of the product from Preparative Example 46 (0.027g, 0.056 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added TEA (0.039 mL, 5 eq.)and AcCl (0.006 mL, 1.2 eq.). The reaction mixture was warmed to roomtemperature and stirred until TLC showed consumption of startingmaterial (20 minutes). The reaction was quenched by the addition ofsaturated NaHCO₃ and extracted with CH₂Cl₂. The combined organics weredried over Na₂SO₄, filtered and concentrated. The crude product waspurified by flash chromatography using a 5% (10% NH₄OH in MeOH) inCH₂Cl₂ solution as eluent to yield a solid mp=60-69° C. LCMS: MH⁺=522.

Examples 104-111

[0325] By essentially the same procedure set forth in Example 103 onlysubstituting the products from Preparative Examples 47-54 shown in Table8, column 2, the compounds shown in column 3 were prepared: TABLE 8 Ex.Column 2 Column 3 Phys. data 104

LCMS: MH⁺ = 468; mp = 49-53° C. 105

LCMS: MH⁺ = 490. 106

LCMS: MH⁺ = 544; mp = 62.1-63.6° C. 107

LCMS: MH⁺ '2 545; mp '2 145.7-147.0° C. 108

LCMS: MH⁺ = 462. 109

LCMS: MH⁺ = 522; mp = 61-63° C. 110

LCMS: MH⁺ = 522; mp = 61-65° C. 111

LCMS: MH⁺ = 564; mp = 61-63° C.

Example 112

[0326]

[0327] To a solution of the product from Preparative Example 52 (0.06 g,0.125 mmol) in CH₂Cl₂ (3 mL) at 0° C. was added TEA (0.087 mL, 5 eq.)and TMSNCO (0.084 mL, 5 eq.). The reaction mixture was stirred until TLCshowed consumption of starting material (30 minutes). The reaction wasquenched by the addition of saturated NaHCO₃ and extracted with CH₂Cl₂.The combined organics were dried over Na₂SO₄, filtered and concentrated.The crude product was purified by flash chromatography using a 5% (10%NH₄OH in MeOH) in CH₂Cl₂ solution as eluent to yield a solid; LCMS:MH⁺=523; mp=95-98° C.

Examples 113-117

[0328] By essentially the same procedure set forth in Example 112 onlysubstituting the products from Preparative Examples 47, 49-50 and 53-54shown in Table 9, column 2, the compounds shown in column 3 (CMPD) wereprepared: TABLE 9 Ex. Column 2 Column 3 CMPD 113

LCMS: MH⁺ = 469; mp '2 80-85° C. 114

LCMS: MH⁺ = 545; mp '2 98.8-102.4° C. 115

LCMS: MH⁺ = 546; mp = 95.2-98.0° C. 116

LCMS: MH⁺ = 523; mp = 91-94° C. 117

LCMS: MH⁺ = 565; mp = 76-80° C.

Example 118

[0329]

[0330] A solution of the product from Preparative Example 33 (0.64mmol), carboxamidopiperadineacetic acid (0.29 g, 1.3 eq.), DEC (0.17 g,1.3 eq.), HOBt (0.12 g, 1.3 eq.), and NMM (0.36 mL, 5.0 eq.) in DMF (8.0mL) was stirred at room temperature 5 days. The reaction was quenched bythe addition of 1N NaOH and extracted with CH₂Cl₂. The combined organicswere dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by flash chromatography using a 15% MeOH in CH₂Cl₂ solutionas eluent (0.13 g, 42% yield); FABMS: MH⁺=471; mp=63-68° C.

What is claimed is:
 1. A compound of the formula (I):

a prodrug thereof, or a pharmaceutically acceptable salt or solvate ofthe compound or of the prod rug wherein, R¹ is selected from the groupconsisting of aryl, heteroaryl, arylalkyl, heteroarylalkyl anddiphenylalkyl, each optionally substituted with one to six groupsselected from the group consisting of: a) halogen; b) —OCF₃ or —OCHF₂;c) —CF₃; d) —CN; e) alkyl or R¹⁸-alkyl; f) heteroalkyl orR¹⁸-heteroalkyl; g) aryl or R¹⁸-aryl; h) heteroaryl or R¹⁸-heteroaryl;i) arylalkyl or R¹⁸-arylalkyl; j) heteroarylalkyl orR¹⁸-heteroarylalkyl; k) hydroxy; l) alkoxy; m) aryloxy; n) —SO₂-alkyl;o) —NR¹¹R¹²; p) —N(R¹¹)C(O)R¹³, q) methylenedioxy; r)difluoromethylenedioxy; s) trifluoroalkoxy; t) —SCH₃ or —SCF₃; and u)—SO₂CF₃ or —NHSO₂CF₃; R² and R³ are each independently selected from thegroup consisting of H, —OH, alkoxy, alkyl, cycloalkyl, heterocycloalkyl,cycloalkylalkyl, trifluoroalkyl, heteroalkyl, arylalkyl,heteroarylalkyl, arylalkoxy, heteroarylalkoxy, —(CH₂)_(n)—NR¹¹R¹² and—(CH₂)_(n)—SR¹¹, provided that when X is N, then R² and R³ are each not—OH, alkoxy, arylalkoxy or heteroarylalkoxy; R⁴, R⁵, R⁷ and R⁸ are eachindependently selected from the group consisting of H, —OR¹⁴, —NR¹¹R¹²,—N(R¹¹)C(O)R¹³, alkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl,

 provided that when Z and/or X is N, then R⁴, R⁵, R⁷ and R⁸ are each not—OR¹⁴, —NR¹¹R¹² or —N(R¹¹)C(O)R¹³; R⁶ is selected from the groupconsisting of —C(O)R¹⁵ and —SO₂R¹⁵; R⁹ and R¹⁰ are each independentlyselected from the group consisting of H, F, —CF₃, —CHF₂, alkyl,cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl,hydroxy, alkoxy, aryloxy, —NR¹¹R¹² and —N(R¹¹)C(O)R¹³, provided thatwhen Z is N, then R⁹ and R¹⁰ are each not F, hydroxy, alkoxy, aryloxy,—NR¹¹R¹² or —N(R¹¹)C(O)R¹³; R¹¹ is selected from the group consisting ofH, alkyl, aryl and heteroaryl; R¹² is selected from the group consistingof H, alkyl, aryl and heteroaryl; R¹³ is selected from the groupconsisting of alkyl, alkoxy and aryloxy; R¹⁴ is selected from the groupconsisting of H, alkyl, aryl and heteroaryl; R¹⁵ is selected from thegroup consisting of —NR¹⁶R¹⁷, —OR¹⁶, alkyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, each optionallysubstituted with R¹⁸; R¹⁶ and R¹⁷ are each independently selected fromthe group consisting of alkyl, aryl, arylalkyl, heteroalkyl andheteroaryl, each optionally substituted with R¹⁸, and H, provided thatwhen R¹⁵ is —OR¹⁶, R¹⁶ is not H; R¹⁸ is one to four substituents eachindependently selected from the group consisting of lower alkyl, halo,cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl,carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl,sulfonamido, aryl and heteroaryl; X and Z are each independentlyselected from the group consisting of C and N; and n is 1-4.
 2. Thecompound of claim 1 wherein, R¹ is selected from the group consisting ofaryl and heteroaryl, each optionally substituted with one to six groupsselected from the group consisting of: a) halogen; b) —OCF₃; c) —CF₃; d)—CN; e) (C1-C20)alkyl or R¹⁸—(C1-C20)alkyl; f) heteroalkyl orR¹⁸-heteroalkyl; g) aryl or R¹⁸-aryl; h) heteroaryl or R¹⁸-heteroaryl;i) arylalkyl or R¹⁸-arylalkyl; j) heteroarylalkyl orR¹⁸-heteroarylalkyl; k) hydroxy; l) alkoxy; m) aryloxy; n) —SO₂-alkyl;o) —NR¹¹R¹²; p) —N(R¹¹)C(O)R¹³; q) methylenedioxy; r)difluoromethylenedioxy; s) trifluoroalkoxy; t) —SCH₃; and u) —SO₂CF₃;R⁴, R⁵, R⁷ and R⁸ are each independently selected from the groupconsisting of H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, —OR¹⁴, —NR¹¹R¹²,

R¹¹ is selected from the group consisting of H and alkyl; Z is C; and nis 1-3.
 3. The compound of claim 1, wherein: R¹ is selected from thegroup consisting of aryl and heteroaryl, each optionally substitutedwith one to six groups selected from the group consisting of: a)halogen; b) —OCF₃; c) —CF₃; e) (C1-C6)alkyl or R¹⁸—(C1-C6)alkyl; f)heteroalkyl or R¹⁸-heteroalkyl; g) aryl or R¹⁸-aryl; i) arylalkyl orR¹⁸-arylalkyl; j) heteroarylalkyl or R¹⁸-heteroarylalkyl; and l) alkoxy;and s) trifluoroalkoxy; R⁴, R⁵, R⁷ and R⁸ are each independentlyselected from the group consisting of H, —OR¹⁴, —NR¹¹R¹², alkyl, aryl,cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl,

R¹¹ is selected from the group consisting of H and alkyl; Z is C; and nis 1-3.
 4. The compound of claim 1 wherein: R¹ is selected from thegroup consisting of aryl and heteroaryl, each optionally substitutedwith one to six groups selected from the group consisting of: a)halogen; b) —OCF₃; c) —CF₃; e) (C1-C6)alkyl or R¹⁸—(C1-C6)alkyl; l)alkoxy; and s) trifluoroalkoxy; R² and R³ are each independentlyselected from the group consisting of H, alkyl, and heteroalkyl; R⁴, R⁵,R⁷ and R⁸ are each independently selected from the group consisting ofH, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, —OR¹⁴, —NR¹¹R¹²

R¹¹ is selected from the group consisting of H and alkyl; and Z is C. 5.The compound of claim 1 wherein, R¹ is selected from the groupconsisting of aryl and heteroaryl, each optionally substituted with oneto six groups selected from the group consisting of: a) halogen; b)—OCF₃; c) —CF₃; l) alkoxy; and s) trifluoroalkoxy; R² is alkyl; R³ is H;R⁴ and R⁵ are each independently selected from the group consisting ofH, (C1-C6)alkyl, heteroalkyl and

R⁷ is selected from the group consisting of H, alkyl, —OR¹⁴ and—NR¹¹R¹²; R⁸ is selected from the group consisting of H, alkyl, aryl andheteroaryl; R¹¹ is selected from the group consisting of H and alkyl;and Z is C.
 6. The compound of claim 1 wherein, R¹ is selected from thegroup consisting of phenyl and pyridyl, each optionally substituted withone to six groups selected from the group consisting of: a) Br, F or Cl;b) —OCF₃; c) —CF₃; l) methoxy, ethoxy or cyclopropylmethoxy; and s)—OCH₂CF₃; R² is selected from the group consisting of methyl, ethyl,propyl, cyclopropylmethyl and t-butyl; R³ is H; R⁴ and R⁵ are eachindependently selected from the group consisting of H, methyl, ethyl,isopropyl and t-butyl; R⁷ is selected from the group consisting of H,—OR¹⁴ and alkyl; R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹⁴ are each independentlyselected from the group consisting of H and alkyl; R¹³ is alkyl; R¹⁵ isselected from the group consisting of —NR¹⁶R¹⁷, —R¹⁶ and alkyl; R¹⁶ andR¹⁷ are each independently selected from the group consisting of H andalkyl; and Z is C.
 7. The compound of claim 1, or the prodrug thereof,or the pharmaceutically acceptable salt or solvate of the compound or ofthe prodrug selected from the group consisting of:


8. The compound according to claim 1, or the prodrug thereof, or thepharmaceutically acceptable salt or solvate of the compound or of theprodrug selected from the group consisting of:


9. The compound according to claim 8, or the prodrug thereof, or thepharmaceutically acceptable salt or solvate of the compound or of theprodrug which is:


10. The compound according to claim 8, or the prodrug thereof, or or thepharmaceutically acceptable salt or solvate of the compound or of theprodrug which is:


11. The compound according to claim 8, or the prodrug thereof, or thepharmaceutically acceptable salt or solvate of the compound or of theprodrug which is:


12. The compound according to claim 8, or the prodrug thereof, or thepharmaceutically acceptable salt or solvate of the compound or of theprodrug which is:


13. The compound according to claim 8, or the prodrug thereof, or thepharmaceutically acceptable salt or solvate of the compound or of theprodrug which is:


14. The compound according to claim 8, or the prodrug thereof, or thepharmaceutically acceptable salt or solvate of the compound or of theprodrug which is:


15. A pharmaceutical composition comprising the compound of claim 1, anda pharmaceutically acceptable carrier therefor.
 16. A method of treatingor preventing an androgen dependent disease, comprising administering toa patient in need thereof a therapeutically effective amount of thecompound of claim 1, or the pharmaceutically acceptable salt or solvatethereof.
 17. The method of claim 16, wherein the androgen dependentdisease is selected from the group consisting of prostate cancer, benignprostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism,acne, androgenic alopecia, polycystic ovary syndrome and combinationsthereof.
 18. The method of claim 17, wherein the androgen dependentdisease is selected from the group consisting of prostate cancer, benignprostatic hyperplasia and prostatic intraepithelial neoplasia.
 19. Amethod of inhibiting 17β-hydroxysteroid dehydrogenases, which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of the compound of claim 1, or the pharmaceutically acceptablesalt or solvate thereof.
 20. A method of treating or preventingandrogen-dependent diseases, comprising administering to a mammal inneed thereof an effective amount of the compound of claim 1 incombination with at least one anti-androgenic agent.
 21. The method ofclaim 20, wherein the anti-androgenic agent is selected from the groupconsisting of inhibitors of 5α-reductase type 1 and/or type 2,flutamide, nicalutamide, bicalutamide, LHRH agonists, LHRH antagonists,inhibitors of 17α-hydroxylase/C17-20 lyase, inhibitors of17β-Hydroxysteroid dehydrogenase/17β-oxidoreductase isoenzymes andcombinations thereof.
 22. A method of treating or preventing benignprostatic hyperplasia, comprising administering to a patient in needthereof a therapeutically effective amount of the compound of claim 1 incombination with at least one other agent useful for the treatment orprevention of benign prostatic hyperplasia.
 23. The method of claim 22,wherein the other agent useful for the treatment or prevention of benignprostatic hyperplasia is an alpha-1 adrenergic antagonist.
 24. A methodof treating or preventing hair loss, comprising administering aneffective amount of the compound of claim 1 in combination with at leastone anti-alopecia agent.
 25. The method of claim 24, wherein theanti-alopecia agent is a potassium channel agonist or a 5α-reductaseinhibitor.
 26. A method of treating or preventing proliferativediseases, comprising administering concurrently or sequentially to amammal in need of such treatment, a therapeutically effective amount ofthe compound of claim 1 in combination with an effective amount of atleast one agent or therapy selected from the group consisting of achemotherapeutic agent, a biological agent, surgery and radiationtherapy.
 27. The method of claim 26, wherein the chemotherapeutic agentis: (a) an antineoplastic agent selected from the group consisting ofUracil mustard, Chlormethine, Cyclo-phosphamide, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Temozolomide, Methotrexate, 5-Fluorouracil,Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabinephosphate, Pentostatine, Gemcitabine, Vinblastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin,Epirubicin, Idarubicin, Paclitaxel (Taxol), Mithramycin,Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons, Etoposide,Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,CPT-11, Anastrazole, Letrazole, Capecitabine, Raloxifine, Droloxifineand Hexamethylmelamine; or (b) a microtubule affecting agent selectedfrom the group consisting of allocolchicine, Halichondrin B, colchicine,colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel,paclitaxel derivatives, thiocolchicine, trityl cysteine, vinblastinesulfate, vincristine sulfate, epothilone A, epothilone, discodermolideestramustine, nocodazole and MAP4; and wherein the biological agent isselected from the group consisting of interferon-α, interferon-β andgene therapy; and wherein the proliferative disease is selected from thegroup consisting of lung cancer, pancreatic cancer, colon cancer, renalcancer, myeloid leukemia, thyroid follicular cancer, myelodysplasticsyndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breastcancer, ovarian cancer, prostate cancer and combinations thereof. 28.The method of claim 27, wherein the proliferative disease is selectedfrom the group consisting of prostate cancer, pancreatic cancer, breastcancer and ovarian cancer; the chemotherapeutic agent is selected fromthe group consisting of Cyclophosphamide, 5-Fluorouracil, Temozolomide,Vincristine, Cisplatin, Carboplatin, Gemcitabine, Taxotere, paclitaxeland/or a paclitaxel derivative, and the biological agent isinterferon-α.